The successful development of targeted therapy for BRAF-mutant melanoma represented a landmark in cancer therapy. However, despite impressive initial responses, most melanoma patients eventually progressed on therapy, necessitating the development of additional therapeutic strategies. Recent studies from our laboratory have identified novel roles for the bromodomain plant homeodomain (PHD) finger transcription factor [BPTF] gene as a mediator of melanoma progression, and as a potential target for therapy. Our studies showed that BPTF activates the MAP kinase pathway, resulting in decreased sensitivity to BRAF inhibitors. Separately, the development of a small molecule inhibitor targeting the BET family has indicated the druggability of bromodomain motifs. In this proposal, we plan to further develop BPTF targeting as a therapeutic strategy for advanced melanoma, especially in combination with available therapies targeting mutant BRAF. Our three specific aims are: Aim 1: To determine the role of BPTF targeting in melanoma therapy. To develop BPTF targeting as a therapeutic strategy for melanoma, we will assess the anti-tumor efficacy of BPTF targeting using (i) bromosporine, a pan-bromodomain inhibitor with demonstrated affinity for BPTF, and (ii) AU1, a novel, small molecule that selectively targets the BPTF bromodomain. We will assess the anti-tumor efficacy of these compounds in a panel of human melanoma cell lines and patient-derived xenografts (PDX) both in culture and in vivo. Aim 2: To determine the role of combined targeting of BPTF and BRAF in melanoma therapy. To develop combined targeting of BPTF and BRAF as a rational strategy for melanoma therapy, we will examine BPTF targeting with bromosporine or AU1 in combination with BRAF pathway inhibition in a panel of human melanoma cell lines and PDXs both in cell culture and in vivo. In addition, we will assess the ability of both BPTF inhibitors to sensitize melanoma PDXs from patients progressing on BRAF inhibitor therapy both in culture and in vivo. Aim 3: To characterize the functional role of BPTF targeting in melanoma cells. We will determine whether BPTF binds to the ERK promoter. We will determine the effects of BPTF targeting (alone or in combination with BRAF inhibitors) on expression of downstream markers in melanoma cells. Finally, we will determine whether targeting BPTF interferes with its interaction with histone modifications. These studies will establish BPTF targeting as a viable strategy for the therapy of melanoma, especially in combination with BRAF inhibitors.